Effect of B7.1 Costimulation on T-Cell Based Immunity against TAP-Negative Cancer Can Be Facilitated by TAP1 Expression

Abstract

Tumors deficient in expression of the transporter associated with antigen processing (TAP) usually fail to induce T-cell-mediated immunity and are resistant to T-cell lysis. However, we have found that introduction of the B7.1 gene into TAP-negative (TAP−) or TAP1-transfected (TAP1+) murine lung carcinoma CMT.64 cells can augment the capacity of the cells to induce a protective immune response against wild-type tumor cells. Differences in the strength of the protective immune responses were observed between TAP− and TAP1+ B7.1 expressing CMT.64 cells depending on the doses of γ-irradiated cell immunization. While mice immunized with either high or low dose of B7.1-expressing TAP1+ cells rejected TAP− tumors, only high dose immunization with B7.1-expressing TAP− cells resulted in tumor rejection. The induced protective immunity was T-cell dependent as demonstrated by dramatically reduced antitumor immunity in mice depleted of CD8 or CD4 cells. Augmentation of T-cell mediated immune response against TAP− tumor cells was also observed in a virally infected tumor cell system. When mice were immunized with a high dose of γ-irradiated CMT.64 cells infected with vaccinia viruses carrying B7.1 and/or TAP1 genes, we found that the cells co-expressing B7.1 and TAP1, but not those expressing B7.1 alone, induced protective immunity against CMT.64 cells. In addition, inoculation with live tumor cells transfected with several different gene(s) revealed that only B7.1- and TAP1-coexpressing tumor cells significantly decreased tumorigenicity. These results indicate that B7.1-provoked antitumor immunity against TAP− cancer is facilitated by TAP1-expression, and thus both genes should be considered for cancer therapy in the future.

A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens

“…Importantly, in this vaccination strategy, TEIPP antigens do not require to be molecularly identified. Finally, others demonstrated that tumor cell vaccines consisting of TAP-impaired tumor cell lines might also induce immune protection, provided that enough co-stimulation on the tumor cell vaccine is at hand [ 46 , 47 ]. The applicability of this variety of therapeutic immune interventions shows that TEIPPs can be exploited alike conventional tumor antigens, despite their unconventional character.…”

Influence of Immune Privilege on Ocular Tumor Development

“…There are multiple mechanisms that tumors employ to establish tumor escape variants including loss of tumor antigen expression by downregulation of (i) MHC class I genes, (51) (ii) antigen processing genes such as the peptide transporter genes TAP1 and TAP2, (52,53) (iii) immunoproteasome genes LMP-2 and LMP-7, (52) or (iv) loss of tumor antigen gene expression. (54–56) Tumors may also directly inhibit immune responses by producing immunosuppressive factors such as IL-10 and TGF-β (57–59) or by the expression of CD95L (FasL) which promotes tumor-specific CD95 (Fas)+ immune cells to undergo apoptosis.…”

Limited Density of an Antigen Presented by RMA-S Cells Requires B7-1/CD28 Signaling to Enhance T-Cell Immunity at the Effector Phase

“…Mouse TAP2-deficient RMA-S cells were transfected with either pUB6-vector or pUB6-based B7-1 cDNA [11] . The transfectants were designated as RMA-S/pUB and RMA-S/B7-1 cells and were maintained in RPMI 1640 (Mediatech Inc., Manassas, VA., USA) supplemented with 10% FCS, 2 mM L-glutamine, 100 IU/ml penicillin, 100 microgram/ml streptomycin and 20 mM HEPES and supplemented with 10 microgram/ml Blasticidin.…”

“…Transporter associated with antigen processing (TAP)-deficient tumors represent immune-escape variants [9] . Presentation of MHC-I-restricted antigen in these tumors is insufficient; therefore, the induction of the T-cell responses is either difficult [10] or less efficient [11] . Introduction of the B7-1 gene into TAP-deficient tumor cells stimulates immune system to generate stronger T-cell mediated immune responses against B7-1 negative parental counterparts [10] – [12] , suggesting that the induction phase of T-cell immunity is augmented by B7-1.…”

“…Recent evidence indicates that CD8 + T cells generated by B7-1 expressing tumor cells recognized a panel of the TAP independent antigens [13] . One of the antigens, Lass5, derived from the ceramide synthase Lass5 (or Trh4/CerS5) protein, located in the endoplasmic reticulum (ER) lumen, associates with H-2D b and is presented by many TAP-deficient, but not TAP-proficient, mouse cells [11] , [13] . Although both TAP-proficient and TAP-deficient mouse cells express Lass5 protein, peptide/D b complexes are selectively presented on TAP-deficient counterparts, most likely due to competition of TAP-mediated peptide antigens [14] .…”